Inhibiting polymethylene diquaternary curariform activity by alpha-stilbazoline derivatives



United States Patent 4 Claims. (Cl. 167-65) The present inventionrelates to a new class of derivatives having the property of inhibitingthe action of certain curariform drugs. These compounds comprise afamily of diquaternary salts having the formula:

wherein R and R are radicals selected from the class consisting of themethyl and ethyl radicals and R is a lower alkyl radical of not overfour carbon atoms, and X- is the anion of a non-toxic acid.

The inhibiting action of these compounds which are derived fromalpha-stilbazoline is entirely unexpected in view of the very potentcurare-like activity of the closely related diquaternary salts of the'y-stilbazoline system such as While the present derivatives show onlyvery minor curate-like activity, they possess the surprising property ofinhibiting the action of their 'y-analogs. This inhibitory action,however, does not extend to natural d-tubocurarine chloride but it doesafiect the powerful polymethylene diquaternary salts of which thebestknown is decarn'ethylene bis-trimethylammonium bromide (DecamethoniumBromide, Syncurine, Ceeten,. C-lO). Since these latter compounds whichare already in clinical use suffer from the disadvantage of having nodirect antidote, the protective utility of our a-stilbazolinediquaternary salts in medicine is considerable.

The compounds of the present invention are conveniently prepared by asequence of reactions parallel to that shown in our co-pending patentapplication No. 218,279, now Pat. No. 2,655,503, on the -y-stilbazolinediquaternary salts.

2,780,577 A, Patented Feb. 5, 1957 base Steps land 11 have already beendescribed (Phillips, J. Org. Chem, 12, 333 (1947), and J. Amer. Chem.Soc., 72, 1850 (1950) wherefore the present application discloses onlythose processes involved in the third step and the preparation ofcertain intermediates not specifically reported before.

In the general formula of these diquaternary salts the III nature of thealkyl groups (R, R and R appears not 7 to be especially critical;however, the simplest compound in which all are methyl groups is atleast as active as any of the others. Further, with increasing size ofthe alkyl groups the respiration is afiected unfavorably and thesynthetic operations become more difficult so that the given limitscover the substances that are believed to be of practical utility. Thecompounds having R =n-propyl and n-butyl with R=R =methyl were notobtained in crystalline form though analytically pure. In part this maybe due to the general tendency of larger alkyl groups to lower meltingpoints; however, other influences may be at work. When all-alkyl groupsare the same these substances have one asymmetric atom and exist asracemic mixtures, but when R and R are ditferent a second point ofasymmetry is created at the piperidine nitrogen. Such substances canexist in four stereo-isomeric forms or as two different racemicmodifications. It is very likely that the lower and unsharp meltingpoints correspond to the presence of such isomeric mixtures. Furtherseparation of isomers will doubtless reveal variations in physiologicalactivity, but it is not believed that such separation will be ofcommercial value.

According to the given scheme of synthesis X- is 1'. However, otheranions can be present. such as Br, SO4= etc. through the use of otheralkylating agents in place of methyl or ethyl iodide. Furthermore, theiodides can readily be converted into other salts by conventionalmethods. In the doses to be used in practice the nature of the anion isof no consequence and therefore we consider all anions of acidspossessing low inherent toxicity to be equivalent and comprehended inour invention.

EXAMPLE 1 1 methyl 2 (4' dimethylaminophenethyl) piperidine bismethiodide (compound 49-204) The base obtained from 12.5 g. (0.033 mole)of 1 methyl 2 (4 dimethylaminophenethyl) piperidine hydroiodide (or 1methyl 4 dimethylamino a stilbazoline hydroiodide) was taken up in etherand dried over potassium carbonate. The solution was filtered from thedesiccant and evaporated. The residual base (8.3 g.) was dissolved inmethanol, 8 cc. of methyliodide was added, and the solution was refluxed8 hours on the steam bath. The solvent and excess methyliodide were thenevaporated and the diquaternary salt was crystallized from a methanolethyl acetate mixture, M. P., 188- 189 C. Conversion to the chloride wasaccomplished by shaking with silver chloride in aqueous solution.

3 EXAMPLE 2 N methyl 2 (4 dimethylaminophenethyl) piperidine bisethiodide (compound 49-241) By the method of Example 1, 1 methyl 2 (4 dimethylaminophenethyl) piperidine was converted to its bis-ethiodidewhich melts at. 205-6.

The corresponding bis n-propiodide and bis n-butiodide were alsoprepared by the same procedure. Although they could not be obtainedcrystalline, they were precipitated a number of times as oils whichhardened on rubbing with ether to apparent solids. These gave correctanalysis for carbon, hydrogen, and iodine and may be regarded asanalytically pure. They may be mixtures of stereoisomers. These solidssoftened over the ranges of 145-l50, and 115-120 C'. respectivelyEXAMPLE. 3

1' methyl 2 (4 diethylaminophenethyl) piperidine bismethiodide The basewas liberated from 6 g. (0.015 mole) of 1 methyl 2 (4diethylaminophenethyl) piperidine, taken into ether and dried overpotassium carbonate. After evaporation of the solvent ether the residuewas dissolved in 15 cc. of methanol and the solution was divided intotwo equal portions. To one of these was added cc. of methyl iodide andthe solution was refluxed 18 hours. The solvent was evaporated and theresidue was crystallized from ethanol-ether mixtures. The product (3.5g.) melted with decomposition at 191- 192 C.

The second portion of the solution of the precursor base was convertedto the his ethiodide. This, like the bis propiodide and his butiodide ofExample 2 could not be crystallized but was obtained as a pseudo solidof correct composition.

omorn-Q-mnnw 2X- N 7 3. A method of checking the curate-like activity ofa polymethylene.diquaternary curariform drug which comprises theadministration to a human being of a salt of the bivalent cation:

4. emeraQarwmncm.

4. A method of checking the curare-like activity of a polymethylenediquaternary curariform drug which comprises the administration to ahuman being of a salt of the bivalent cation:

omcmQ-mcnmum References Cited in the file of this patent Phillips. (1):J. Org. Chem., vol. 14, pp. 302-5 (1949).

Phillips (II): J. Am. Chem. Soc., vol. 72, pp. 1850-2, April 1950.

1. A METHOD OF CHECKING THE CURARE-LIKE ACTIVITY OF A POLYMETHYLENEDIQUATERNARY CURARIFORM DRUG WHICH COMPRISES THE ADMINISTRATION TO AHUMAN BEING OF A COMPOUND OF THE FORMULA